Cognito’s Gamma Sensory Stimulation Leads to Preserved Corpus Callosum Structure in Alzheimer Disease

Ralph Kern, MD, MHSc

At the 2025 AD/PD International Conference on Alzheimer’s and Parkinson’s Diseases, held April 1-5 in Vienna, Austria, Cognito Therapeutics presented a pair of posters highlighting its gamma sensory stimulation device in patients with Alzheimer disease. In these data, findings showed that sensory stimulation delivered by Spectris effectively evoked 40 Hz steady-state oscillation, and led to preserved corpus callosum (CC) area structure when compared with matched participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI).¹

The first analysis compared total and regional CC changes in patients from the previously conducted OVERTURE study (NCT03556280) to a matched ADNI cohort. To ensure baseline comparability with ADNI controls, OVERTURE participants with Mini-Mental State Examination (MMSE) scores of 21-26 were selected. After 6 months of treatment with Spectris, a non-invasive neuromodulation device, patients demonstrated significant preservation of the total CC area and its subregions (genu/rostrum, anterior body, mid body, posterior body, splenium). Overall, the difference in percentage change in total CC area between active and sham groups were 2.28 (±0.87; P <.02).

"The corpus callosum is critical for brain connectivity, serving as a major white matter structure that links the two hemispheres," Ralph Kern, MD, MHSc, chief medical officer at Cognito, told NeurologyLive. "In Alzheimer disease, its size and integrity decline over time. What we’re seeing with our device is structural preservation, which suggests a potential impact on myelin and white matter health—areas that have been largely overlooked in previous treatments."

After 6 months of treatment, those on the Spectris device demonstrated a total CC area change of 0.58% (±0.43), whereas those in the baseline-matched ADNI group showed changes of –0.91% (±0.26), leading to a statistically significant difference (1.49 [±0.51]; P <.004) between the cohorts. Detailed analyses showed significant differences in specific subregions of CC, including genu/rostrum (1.52% [±0.54]; P <.006), anterior-body (1.69 [±0.95]; P <.045), and splenium (1.25% [±0.48]; P <.010). Of note, mid-body difference (0.94% [±0.77]) was not statistically significant.

"An active brain is a healthy brain," Kern added. "Neurons that fire together, wire together—and more recently, we’ve learned they also ‘shower together,’ meaning their oscillating activity drives the brain’s waste removal system. Our device is designed to restore these disrupted rhythms in Alzheimer disease, promoting brain resilience and function."

The second analysis examined whether MRI measurements correlate with measures of sensory evoked 40 Hz gamma oscillation in patients with AD from the OVERTURE study. A total of 76 patients with baseline EEG and MRI data were included, while the 30-channel EEG data was down-sampled to 512 Hz, filtered 1 to 100 Hz, re-referenced to REST, and had line noise removed. The Phase Locking Index (PLI) was calculated to quantify the phase coherence between the stimulus and the EEG response at the stimulation frequency of 40 Hz.

All told, results showed that cortical and white matter volumes correlated with power and phase locking of sensory-evoked gamma oscillation. In addition, temporal lobe volume and cortical thickness, as well as occipital lobe volume and cortical thickness, also linked with power and phase locking of sensory-evoked gamma oscillation. Furthermore, findings revealed that age has a weak or no correlation with power and phase locking of sensory-evoked gamma oscillation from Spectris.

READ MORE: Patient-Informed Phase 2 ATLANTIS Study Tests Selective D1PAM Agent Glovadalen for Parkinson Disease

At the 2023 Clinical Trials on Alzheimer’s Disease (CTAD) conference, 18-month data from OVERTURE highlighted the impacts of the gamma sensory stimulation approach in slowing AD progression. In the open-label extension, a mean total of 422.27 days to reach at least a 15% decline in Alzheimer’s Disease Cooperative Study­-Activities of Daily Living (ADCS-ADL) total score was recorded for those on the stimulation device vs 150.96 days for those on sham. In addition, continued treatment with the therapy showed a lower rate of brain atrophy than that observed in the sham arm during the randomized controlled period and OLE.

Cognito is currently in the final stages of recruitment for its phase 3 HOPE study testing the gamma sensory stimulation device in a large cohort of 670 patients with mild-to-moderate AD. This multicenter, double-blind, sham-controlled, adaptive pivotal study will use Alzheimer’s Disease Cooperative Study-Activities of Daily Living assessment and a combined statistical test of the ADCS-ADL and the Mini-Mental State Exam as means to test efficacy. This 12-month study will include patients with MMSE scores between 15-28, using measures of cognition and neuroanatomical change as secondary end points.

Kern added, "We’re using physics to treat brain chemistry and biology, leveraging sensory stimulation to drive brain-wide changes. The support we’ve received from the Alzheimer’s community reflects growing excitement around this innovative approach, and we’re eager to see how it translates into clinical outcomes."

Click here for more AD/PD 2025 coverage.

REFERENCES
1. Kern R, Lee L, Cimenser A, Hajos M, Bendlin BB. SPECTRIS™ TREATMENT PRESERVES CORPUS CALLOSUM STRUCTURE IN ALZHEIMER'S DISEASE: A COMPARATIVE STUDY. Presented at: 2025 AD/PD conference; April 1-5. ABSTRACT 2054
2. Hajos M, Jackson BL, Hernandez M, Rowe O, Seshagiri C, Kern R. SENSORY EVOKED GAMMA OSCILLATION CORRELATES WITH BRAIN MORPHOLOGY IN ALZHEIMER’S DISEAE. Presented at: 2025 AD/PD conference; April 1-5. ABSTRACT 2000.
3. Cognito Therapeutics presents phase 2 OVERTURE study open-label extension data showing safety, adherence and durability of treatment benefits over 18 months. News release. October 24, 2023. Accessed April 3, 2025. https://www.businesswire.com/news/home/20231024308538/en/Cognito-Therapeutics-Presents-Phase-2-OVERTURE-Study-Open-Label-Extension-Data-Showing-Safety-Adherence-and-Durability-of-Treatment-Benefits-Over-18-Months